Phlorotannins

Tannins are naturally occurring water-soluble polyphenolic compounds, and it has been reported that they show their anti-HIV activity by inhibiting polymerase and ribonuclease activities of HIV-1 RT. Phlorotannins are tannin derivatives which contain several phloroglucinol units linked to each other in different ways and formed by the polymerization of phloroglucinol (1,3,5-trihydroxybenzene) monomer units and biosynthesis through the acetate-malonate pathway. So far, phlorotannins mostly have been isolated from red and brown alga. Numerous bioactivities of phlorotannins have been reported up to date such as antioxidant, anti-inflammatory, antibacterial, and anti-MMP activities (Kim et al., 2006; Nagayama et al., 2002).

For the first time, seaweeds extracts have been tested for their anti-HIV-1 activity in terms of inhibiting RT, protease, and integrase of HIV-1 (Ahn et al., 2004). Following the mentioned research, two phlor-otannins from brown alga Ecklonia cava Kjellman have been isolated and reported to inhibit the HIV-1 protease and RT. These pholorotannins, 8,8'-bieckol and 8,4'"-dieckol, which are dimers of eckol, isolated from E. cava, inhibited the RT and protease activity efficiently. In case of inhibition of HIV-1 RT, 8,8'-bieckol which has a biaryl linkage showed a 10-fold higher activity than that of 8,4'''-dieckol which has a diphenyl ether linkage with the IC50 values of 0.5 and 5.3 p.M, respectively. Hence the significant RT inhibitory activity of 8,8'-bieckol was favorable against its protease inhibition and comparable to the positive control nevirapine which has an IC50 value of 0.28 p.M. In the light of recent reports, 8,8'-bieckol might be employed as a drug candidate for development of new generation therapeutic agents against HIV. In addition to these results, in another report, 6,6'-bieckol from E. cava reduced the cytopathic effects of HIV-1 including HIV-1-induced syncytia formation and viral p24 antigen levels, as well as inhibited RT and HIV-1 entry activity (Artan et al., 2008). It has been strongly suggested that 6,6'-bieckol is a safe tannin derivative exhibiting a relatively lower cytotox-icity in comparison to other polyphenols and significant anti-HIV-1 activity. In detail, 6,6'-bieckol protected 96% of the HIV-1 infected cells from infection-induced lytic effects and inhibited the syncytia formation up to 88% with an EC50 value of 1.72 p.M. Moreover, 6,6'-bieckol inhibited the RT activity and p24 production with IC50 values of 1.07 and 1.26 mM, respectively. The performed studies also clearly showed that addition of 6,6'-bieckol successfully prevented the HIV-1 entry dependent on the inhibition of production of specific proteins such as p55 and p41. These results were strengthening by coculture assays which again show clear inhibitory effect against HIV-1 infection in vitro. This important anti-HIV activity in various stages of viral cycle including viral entry and RT activity, however, excluding a sufficient protease inhibition, promotes 6,6'-bieckol as a significant lead for further drug design on the way to a full inhibition of HIV-1 activity.

Besides the brown alga E. cava, another phlorotannin, diphlorethohy-droxycarmalol has been isolated from Ishige okamurae Yendo (Ahn et al., 2006). This phlorotannin was assayed for its inhibitory activity against HIV-1 RT, integrase, and protease while any study for its HIV-1 activity in vitro has not been carried out. Diphlorethohydroxycarmalol inhibited the RT and protease activity with IC50 values of 9.1 and 25.2 p.M, respectively; however, it failed to show any efficiency against HIV-1 protease. Therefore, this phlorotannin also can be regarded as an important compound for anti-HIV drug designing, or nutraceutical and pharmaceutical industries.

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